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Abstract
Purpose: The role of cardiac mast cells (MC) in the progression to heart failure has recently become increasingly evident. Previously, two types of MCs have been described: MCs with the protease tryptase (MCT), and the subtype with the proteases tryptase and chymase (MCTC). Cathepsin g is a neutrophiland MC-derived protease, and like chymase, it can convert angiotensin I to angiotensin II and thereby activate the TGFpathway resulting in myocyte necrosis, hypertrophy and increased fibrosis. This study focuses on MC-derived cathepsin g in the human heart, during heart failure and following mechanical unloading by means of LVADs. Methods and Materials: Myocardial tissue was obtained from 10 patients with end-stage cardiomyopathy at the time of LVAD implantation (preLVAD) and following orthotopic heart transplantation (post-LVAD). In addition, biopsies of 4 normal hearts served as a control group. Paraffin embedded sections were dual stained for cathepsin g and tryptase, as well as chymase and cathepsin g, using standard immunohistochemistry protocols. Total positive (pos.) mast cells per section were counted. Results: No cathepsin g or chymase pos. MCs were found in normal hearts. However, we found evidence for cathepsin g in cardiac MCs in heart failure tissues (Pre-LVAD). During heart failure 46% of total MCs were cathepsin g pos. as compared to after mechanical unloading where only 11% of total MCs were cathepsin g pos. (p 0.001). Cathepsin g was co-localized in the MCTC subtype. Conclusions: Heart failure causes an increase of myocardial MCs. We have provided evidence that cathepsin g pos. MCs accumulate during heart failure and their total percentage decreases after ventricular unloading. This coincides with the decrease in myocyte necrosis, hypertrophy and fibrosis. Thus, cathepsin g may play a role in the progression to heart failure due to similar formation of angiotensin II as chymase. Both MC proteases should be future therapeutic targets, in order to reverse the progression of heart failure.
Published Version
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